不适合移植的大 B 细胞淋巴瘤二线使用 axicabtagene ciloleucel：ALYCANTE 最终分析
Second-line axicabtagene ciloleucel in large B-cell lymphoma ineligible for transplantation: ALYCANTE final analysis.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
免疫通路上调与较低的基因组不稳定性可将 EBV 阳性结内 T/NK 细胞淋巴瘤与 ENKTL 和 PTCL-NOS 区分开来
英文原题：Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS.
查看英文原题
Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS.
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中文摘要
原发性EBV阳性结内T/NK细胞淋巴瘤（PTCL-EBV）是一种认识不足的疾病，其表现特征与结外NK/T细胞淋巴瘤（ENKTL）相似，目前尚未被认定为一个独立病种，而是被归类为原发性T细胞淋巴瘤非特指型（PTCL-NOS）的一种变异型。
在此，我们分析了拷贝数畸变（n=77），重点关注基因组不稳定性和同源重组缺陷的整体指标，并进行了基因表达（n=84）和EBV miRNA表达（n=24）谱分析以及靶向突变分析（n=16），以进一步刻画PTCL-EBV相对于ENKTL和PTCL-NOS的特征。多因素分析显示，PTCL-EBV患者的预后显著差于PTCL-NOS患者（P=0.002），但与ENKTL患者相比无显著差异。
值得注意的是，与ENKTL和PTCL-NOS相比，PTCL-EBV表现出显著更低的基因组不稳定性评分和同源重组缺陷评分。基因集富集分析显示，许多免疫相关通路、干扰素α/γ应答以及IL6_JAK_STAT3信号在PTCL-EBV中显著上调，并与较低的基因组不稳定性评分相关。
我们还发现NFκB相关基因BIRC3、NFKB1（P50）和CD27及其蛋白在PTCL-EBV中上调。大多数PTCL-EBV表现为2型EBV潜伏模式，并且引人注目的是，与ENKTL相比，大多数EBV miRNA表达下调，其靶基因也富集于免疫相关通路。PTCL-EBV还显示TET2、PIK3CD和STAT3的频繁突变，并以微卫星稳定为特征。
总体而言，预后差、基因组不稳定性低、免疫通路上调和EBV miRNA下调是PTCL-EBV的显著特征。我们的数据支持PTCL-EBV可被视为一个独立实体的概念，为该病的发病机制提供了新的见解，并为该肿瘤提供了潜在的新治疗靶点。
展开英文摘要原文
Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS).
Herein, we analyzed copynumber aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.
002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCLEBV and correlated with lower genomic instability scores.
We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability.
Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV.
Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.
论文信息
- 作者
- Wai CMM、Chen S、Phyu T、Fan S、Leong SM、Zheng W、Low LCY、Choo SN
- 第一作者单位
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.Singapore
- 通讯作者单位
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pathology, National University Hospital, National University Health System, Singapore. patnsb@nus.edu.sg.Singapore
- 期刊
- Haematologica2022 Aug 1
- 原文标识
- PubMed 35021606 · DOI 10.3324/haematol.2021.280003